丹参、美托洛尔对大鼠心肌缺血坏死区干细胞修复的影响

目的：探讨丹参（danshen）、美托洛尔（metoprolol）药物干预对异丙肾上腺素诱导大鼠心缺血坏死区干细胞修复的影响.方法：健康SD大鼠40只,按4mg/kg的剂量连续腹腔注射盐酸异丙肾上腺素（ISO）7 d制备大鼠心肌缺血模型,将造模成功的32只大鼠随机分为4组,异丙肾上腺素对照组（ISO组）,丹参干预组（Danshen组）,美托洛尔干预组（Meto组）,丹参＋美托洛尔联合干预组（Danshen＋-Meto组）.H-E染色比较各组心室肌缺血坏死区大小、免疫荧光观察缺血坏死区c-kit、CD34干细胞标记物及心肌早期转录因子GATA-4和心肌缝隙连接蛋白connexin 43的表达情况.结果：与ISO组比较,其他3组大鼠心肌组织H-E染色心室内膜下缺血面积减小,免疫荧光观察显示缺血区及缺血周边表面标记物c-kit、CD34阳性干细胞增多,缺血区可观察到GATA-4及connexin 43的表达.结论：丹参、美托洛尔能促进心肌缺血坏死区干细胞的迁移和增殖,并最终形成具心肌细胞特征的“心肌样细胞”.

不同左旋聚乳酸支架微结构对心源干细胞增殖、分化的影响

目的探讨不同空间微结构的左旋聚乳酸(PLLA)支架材料对心源干细胞增殖、分化的作用,筛选出性能优异的PLLA支架微结构。方法将三种不同微结构[层状结构(LS)、球体结构(MS)、纳米纤维结构(NS)]的PLLA支架各56个经酒精及紫外线消毒灭菌后,分别置入96孔板中,随后在96孔板种植相同数量的心源性干细胞,三种材料支架互相对照。采用MTT法检测细胞活力;取培养1周的三种微结构材料行共焦显微镜检测及扫描电镜检测,观察干细胞的增殖、分化情况。结果三种微结构材料支架均能促进心源性干细胞的增殖,从第48 h开始,细胞在NS中增殖速度最快,其次为MS,最后为LS,两两组间比较差异均有统计学意义(P<0.05);三种材料的单位有效接触面积内吸光度随培养时间增长而增加,并且两相邻时间点的增殖差异有统计学意义(P<0.05)。结论三种微结构均能促进干细胞的增殖、分化,其中纳米纤维结构效果最优,可作为心肌组织工程研究的优先选择。

Effect of Fufang Danshen Pill on Bone Marrow Stem Mobilization when Myocardial Scathe

Objective：To investigate the effect of Fufang Danshen pill on bone marrow stem mobilization during myocardial scathe. Methods：Rat models with expansionary myocardial disease were established by Pituitrin and Furazolidone. Experimental rats were divided into the contrast group, the myocardial scathe group （MS group）, the myocardial scathe and Fufang Dansben pill group （ MS ＋ FD group） and the myocardial scathe and fluvastatin group （ MS ＋ FT group）. The ratio of CD34^＋ cells was examined at the 1^st, 3^nl and 6^th weekend. Index of heart structure and function including LVESD, LVEDD. LYEF, LVEDP and dp/dtmax were evaluated at the 6^th weekend. The HW/BW index was calculated. Results：In the MS group, the index of HW/BW, LVESD, LVEDD and LVEDP were obviously increased （P 〈 0.01 ） and index of dp/ dtmax and LVEF were obviously decreased （P 〈 0.05 ）. The ratio of CD34^＋ cells was significantly improved at the 1^at weekend and then reduced slowly with no difference from that of the contrast group at the 6th weekend. Compared the MS ＋ FD group and the MS ＋ FT group with the MS group, the index of HW/BW, LYESD, LYEDD and LYEDP of were signifi cantly decreased （ P 〈 0.05 ） and index of dp/dtmax and LVEF were increased （P 〈 0.01 ）. The ratio of CD34^＋ cells was significantly higher at the 1^st, 3^nl and 6^th weekend, but had no statistic meaning at 3^nl and 6^th weekend （P 〉 0.05 ）. Conclusion：Pituitrin and Furazolidone can be used to establish rat models with expansionary myocardial disease. There has bone marrow stem mobilization during the early period of myocardial scathe. Fufang Danshen pill has effect on improving bone marrow stem mobilization, lightening the expansionary degree of heart and protecting the heart function. The effect of Fufang Danshen pill is as same as that of fluvastatin.

5-Azacytidine induces changes in electrophysiological properties of human mesenchymal stem cells

Previously, mouse bone marrow-derived stem cells （MSC） treated with the unspecific DNA methyltransferase inhibitor 5-azacytidine were reported to differentiate into cardiomyocytes. The aim of the present study was to investigate the efficiency of a similar differentiation strategy in human mononuclear cells obtained from healthy bone marrow donors. After 1-3 passages, cultures were exposed for 24 h to 5-azacytidine （3 μM） followed by 6 weeks of further culture. Drug treatment did not induce expression of myogenic marker MyoD or cardiac markers Nkx2.5 and GATA-4 and did not yield beating cells during follow-up. In patch clamp experiments, approximately 10-15% of treated and untreated cells exhibited L-type Ca^2＋ currents. Almost all cells showed outwardly rectifying K^＋ currents of rapid or slow activation kinetics. Mean current amplitude at ＋60 mV doubled after 6 weeks of treatment compared with time-matched controls. Membrane capacitance of treated cells was significantly larger than in controls 2 weeks after treatment and remained high after 6 weeks, Expression levels of mRNAs for the K^＋ channels Kv 1,1, Kv 1,5, Kv2,1, Kv4,3 and KCNMA 1 and for the Ca^2＋ channel Cav 1.2 were not affected by 5-azacytidine. Treatment with potassium channel blockers tetraethylammonium and clofilium at concentrations shown previously to inhibit rapid or slowly activating K^＋ currents of hMSC inhibited proliferation of these cells. Our results suggest that despite the absence of differentiation ofhMSC into cardiomyocytes, treatme.nt with 5-azacytidine caused profound changes in current density.

Bone marrow mesenchymal stem cell transplantation combined with perindopril treatment attenuates infarction remodelling in a rat model of acute myocardial infarction

Objective: This study was performed to evaluate whether implantation of mesenchymal stem cell (MSC) would reduce left ventricular remodelling from the molecular mechanisms compared with angiotensin-converting enzyme inhibitors (ACEIs) perindopril into ischemic myocardium after acute myocardial infarction. Methods: Forty rats were divided into four groups: control, MSC, ACEI, MSC+ACEI groups. Bone marrow stem cell derived rat was injected immediately into a zone made ischemic by coronary artery ligation in MSC group and MSC+ACEI group. Phosphate-buffered saline (PBS) was injected into control group. Perindopril was administered p.o. to ACEI group and MSC+ACEI group. Six weeks after implantation, the rats were killed and heart sample was collected. Fibrillar collagen was observed by meliorative Masson’s trichome stain. Western Blotting was employed to evaluate the protein expression of matrix metalloproteinase (MMP)-2, matrix metalloproteinase (MMP)-9 in infarction zone. The transcriptional level of MMP2, MMP9 and tissue inhibitor of matrix metalloproteinase (TIMP)-1 in infarction area was detected by reverse transcriptase PCR (RT-PCR) analysis. Results: The fibrillar collagen area, the protein expression of MMP2, MMP9 and the transcriptional level of MMP2, MMP9 mRNA in infarction zone reduced in MSC group, ACEI group, and MSC+ACEI group. No significant difference was detected in the expression of TIMP1 mRNA among the 4 groups. Conclusion: Both MSC and ACEI could reduce infarction remodelling by altering collagen metabolism.

Short- and Long-term Therapeutic Efficacies of Intravenous Transplantation of Bone Marrow Stem Cells on Cardiac Function in Rats with Acute Myocardial Infarction:A Meta-analysis of Randomized Controlled Trials

Objective To investigate the short- and long-term therapeutic efficacies of intravenous transplantation of bone marrow stem cells(MSCs) in rats with experimental myocardial infarction by metaanalysis.Methods Randomized controlled trials were systematically searched from Pub Med,Science Citation Index(SCI),Chinese journal full-text database(CJFD) up to December 2014.While the experimental groups(MSCs groups) were injected MSCs intravenously,the control groups were injected Delubecco's minimum essential medium(DMEM) or phosphate buffered saline(PBS).Subgroup analysis for each outcome measure was performed for the observing time point after the transplantation of MSCs.Weighted mean differences(WMD) and 95% confidence intervals(CI) were calculated for outcome parameters including ejection fraction(EF) and fractional shortening(FS),which were measured by echocardiogram after intravenous injection and analyzed by Rev Man 5.2 and STATA 12.0.Results Data from 9 studies(190 rats) were included in the meta-analysis.As compared to the control groups,the cardiac function of the experimental groups were not improved at day 7(EF:WMD=0.08,95%CI-1.32 to 1.16,P>0.01; FS:WMD=-0.12,95%CI-0.90 to 0.65,P>0.01) until at day 14 after MSCs' transplantation(EF:WMD=10.79,95%CI 9.16 to 12.42,P<0.01; FS:WMD=11.34,95%CI 10.44 to 12.23,P<0.01),and it lasted 4 weeks or more after transplantation of MSCs(EF:WMD=13.94,95%CI 12.24 to 15.64,P<0.01; FS:WMD=9.64,95%CI 7.98 to 11.31,P<0.01).Conclusion The therapeutic efficacies of MSCs in rats with myocardid infarction become increasing apparent as time advances since 2 weeks after injection.

Progress in the treatment of myocardial infarction with stem cells transplantation

Embryonic stem cells and adult stem cells derives from bone marrow, muscule, liver, skin, nerve, adiposes and other tissues or organs are pluripotent. Embryonic stem cells in vitro can differentiate into derivatives of all three embryonic germ layers when transferred to an in vitro environment, and have the ability to form any fully differentiated cells of the body. A series of remarkable studies suggested that adult stem cells undergo novel patterns of development named as transdifferentiation. All of them can be induced into cardiomyocytes in a certain condition and used to treat myocardial infarction. In this review, progress in the treatment of myocardial infarction with stem cells transplantation is summarized.

Cardiotrophin-1 promotes cardiomyocyte differentiation from mouse induced pluripotent stem cells via JAK2/STAT3/Pim-1 signaling pathway

Background The induced pluripotent stem cell （iPSC） has shown great potential in cellular therapy of myocardial infarction （MI）, while its application is hampered by the low efficiency of cardiomyocyte differentiation. The present study was designed to investigate the effects of cardiotrophin-1 （CT-1） on cardiomyocyte differentiation from mouse induced pluripotent stem cells （miPSCs） and the underlying mechanisms involved. Methods The optimal treatment condition for cardiomyocyte differentiation from miPSCs was established with ideal concentration （10 ng/mL） and duration （from day 3 to day 14） of CT-1 administration. Up-regulated expression of cardiac specific genes that accounted for embryonic cardiogenesis was observed by quantitative RT-PCR. Elevated amount of a-myosin heavy chain （ct-MHC） and cardiac troponin I （cTn I） positive cells were detected by immunofluorescence staining and flow cytometry analysis in CT- 1 group. Results Transmission electron microscopic analysis revealed that cells treated with CT- 1 showed better organized sacromeric structure and more mitochondria, which are morphological characteristic of matured cardiomyocytes. Western blot demonstrated that CT-1 promotes cardiomyocyte differentiation from miPSCs partly via JAK2/STAT3/Pim-1 pathway as compared with control group. Conclusions These findings suggested that CT-1 could enhance the cardiomyocyte differentiation as well as the maturation of mouse induced pluripotent stem cell derived cardiomyocytes by regulating JAK2/STAT3/Pim-1 signaling pathway.

Mesenchymal Stem Cells Express Low Levels of Cardiomyogenic Genes and Show Limited Plasticity towards Cardiomyogenic Phenotype

Mesenchymal stem cell differentiation towards osteogenic, chondrogenic and adipogenic lineages have been extensively described and reproduced in the literature. In contrast, cardiomyogenic differentiation still remains largely controversial. In this study the authors aim to shed new light into this unclear phenomenon and test whether BMMSC （bone marrow mesenchymal stem cells） and ATMSC （adipose tissue derived mesenchymal stem cells） are able to differentiate into functional cardiomyocytes, investigating two differentiation protocols. AT and BMMSC behaved differently when cultured in differentiation media and presented lower levels of proliferation and alkaline phosphatase production, expression of cardiomyocyte-specific transcription factors such as GATA-4, Nkx2-5 and proteins such as ct and 13 Myosin Heavy Chains. Furthermore, MSC started to express higher levels of Connexin-43 and c~ sarcomeric actinin protein. Unfortunately, though, MSC did not present cardiomyocyte-like electrophysiological properties. In order to analyze a possible explanation for such limited plasticity, the authors decided to address the issue using a quantitative approach. Gene expression was quantified by Real time PCR, and, for the first time, the authors show that a possible explanation for limited plasticity of MSC is that even though differentiated cells presented differential gene expression, the levels of key cardiomyogenic genes did not reach expression levels presented by adult cardiomyocytes, nor were maintained along differentiation, reaching peaks at 4 days of stimulation, and decaying thereafter.

The Experimental Study on Constructing the Tissue Engineered Myocardium-like Tissue in vitro with Bone Mesenchymal Stem Cells

Objective:Unlike other tissues,myocardium has not substitute whick can be used to repair damaged cardiac tissue.This paper proposes engineering 3-D myocardium-like tissue constructs in vitro with bone mesenchymal stem cells(BMSCs) of infant and poly-lactic-co-glycolic acid(PLGA)in vitro.Methods:Bone marrow was obtained from the sternal marrow cavum outflow of infant with congenital heart disease (CHD)undergoing cardiac operation.BMSCs were obtained by density gradient centrifugation.The cells in passages two were induced in DMED with 10 umol/L 5- Azacytidine(5-Aza)for 24 h.When the induced BMSCS were cultured nearly into filled,the cells were planted in the scaffold of PLGA in 5.5×106 cells/cm2.The cell- scaffold complex has been cultured in the shake cultivation for 1 week,then the complex has been planted in the dorse of the nude mouse.When the experiment had been finished,the histology,immunology,real time PCR and so on were done.Results: The BMSCs of infant with congenital heart disease have the properties of the stable growth and the rapid proliferation.The immunohistochemistry showed that tissue engineered myocardium constructed in vitro expressed some cardiac related proteins such asα-actin,Cx-43,Desmine,cTNI and so on.The transparent myofilaments,gap junctions and intercalated disk-like structure formation could be observed in the 3D tissue-like constructs by transmission electron microscope(TEM).The engineered myocardium-like tissue had the auto-myocardial property as assessed by real time- PCR and so on.Conclusion:The engineered myocardial tissue-like constructs could be built with infant BMSCs and PLGA in vitro.Our results may provide the first step on the long road toward engineering myocardial material for repairing the defect or augmenting the tract in CHD,such as ventricular septal defect,tetralogy of Fallot and so on.

Intravenously Injected Mesenchymal Stem Cells Home to Infarcted Myocardium Without Altering Cardiac Function

Background:Systemic delivery of mesenchymal stem cells (MSCs) to the infarcted myocardium is an attractive noninvasive strategy, but therapeutic effect of this strategy remain highly controversial. Methods: Myocardial infarction was induced in female Sprague-Dawley rats by transient ligation of the left anterior descending coronary artery for 60 min. Either 2.5×106 DiI-labeled MSCs or equivalent saline was injected into the tail vein at 24 h after infarction.Results: Three days later, MSCs localized predominantly in the infarct region of heart rather than in the remote region. MSCs were also observed in spleen, lung and liver. At 4 weeks after infarction, echocardiographic parameters, including ejection fraction, fractional shortening, left ventricular end-diastolic and end-systolic diameters, were not significantly different between MSCs and saline groups. Hemodynamic examination showed that ±dp/dtmax were similar between MSCs and saline-treated animals. Histological evaluation revealed that infarct size and vessel density were not significantly changed by MSCs infusion.Conclusion: Intravenously injected MSCs can home to infarcted myocardium, but plays a limited role in cardiac repair following myocardial infarction.

Safety and effect of umbilical cord blood -derived mesenchymal stem cells on apoptosis of human cardiomyocytes

Objective To study the safety and effect of the umbilical cord blood （UCB）-derived mesenchymal stem cells （MSCs） on apoptosis of human cardiomyocytes （HCM）. Methods UCB was collected at the time of delivery with informed consent obtained from 10 donors. The UCB-derived MSCs were treated with 5-azaserube （5-AZA） and were further induced to differentiate into cardiomyocytes. Telomerase activity, G-banding patterns of chromosomal karyotypes, tumor formation in nude mice, RT-PCR, and the effect of inhibiting apoptosis of HCM were investigated. Results MSCs derived from UCB were differentiated into cardiomyocytes in vitro, which possessed telomerase activity after 5-AZA induction, and no abnormal chromosomal karyotypes were observed. Expression of p53, cyclin A, cdk2, ~3 -actin, C-fos, h-TERT and c-myc were similar in MSCs before and after 5-AZA treatment. There was no tumor formation in nude mice after injection of UCB-derived MSCs. UCB-derived MSCs significantly inhibited apoptosis of HCM. Conclusion UCB-derived MSCs are a valuable, safe and effective source of cell-transplantation treatment .

Application of modified polyethylene glycol hydrogels in the construction of tissue engineered heart valve

To enhance the adhesion of seeding-cells to the biomaterial scaffolds, the PEG-hydrogels were modified. Porcine aortic valves were decellularized with Triton X-100 and trypsin. The cells were encapsulated into the PEG-hydrogels to complete the process of the cells attaching to the acellular porcine aortic valves. Herein, the autologous mesenchymal stem cells （MSCs） of goats were selected as the seeding-cells and the tendency of MSCs toward differentiation was observed when the single semilunar TEHV had been implanted into their abdominal aortas. Furthermore, VEGF, TGF-β1, and the cell adhesive peptide motif RGD were incorporated. Light and electron microscopy observations were performed. Analysis of modified PEG-hydrogels TEHV＇s （PEG-TEHV） tensile strength, and the ratio of reendothelial and mural thrombosis revealed much better improvement than the naked acellular porcine aortic valve （NAPAV）. The data illustrated the critical importance of MSC differentiation into endothelial and myofibroblast for remodeling into native tissue. Our results indicate that it is feasible to reconstruct TEHV efficiently by combining modified PEG-hydrogels with acellular biomaterial scaffold andautologous MSCs cells.

Timing of transplantation of autologous bone marrow derived mesenchymal stem cells for treating myocardial infarction

It is still unclear whether the timing of intracoronary stem cell therapy affects the therapeutic response in patients with myocardial infarction.The natural course of healing the infarction and the presence of putative homing signals within the damaged myocardium appear to favor cell engraftment during the transendothelial passage in the early days after reperfusion.However,the adverse inflammatory environment,with its high oxidative stress,might be deleterious if cells are administered too early after reperfusion.Here we highlight several aspects of the timing of intracoronary stem cell therapy.Our results showed that transplantation of bone marrow mesenchymal stem cells at 2 4 weeks after myocardial infarction is more favorable for reduction of the scar area,inhibition of left ventricular remodeling,and recovery of heart function.Coronary injection of autologous bone marrow mesenchymal stem cells at 2 4 weeks after acute myocardial infarction is safe and does not increase the incidence of complications.

Telomeres,cardiovascular aging,and potential intervention for cellular senescence

A consistent association has been observed between leukocyte telomere length(LTL)and atherosclerosis,but the mechanisms underlying these associations are still not well understood.Premature biology aging was evident in atherosclerotic plaques,characterized by reduced cell proliferation,irreversible growth arrest and apoptosis,and telomere attrition.As atherosclerosis is a state of chronic low-grade inflammation and increased oxidative stress,shortened LTL in patients with atherosclerosis might stem from the two sources,one is an accelerated rate in hematopoietic stem cells(HSCs)replication to replace leukocytes consumed in the inflammatory process,and another is the increase in the loss of telomere repeats per replication.Thus,diminished HSC reserves at birth and age-dependent telomere attrition afterward are mirrored in shortened LTL during the adulthood.In addition,the inter-individual variation of LTL in the general population can be partly explained by genetic factors regulating telomere maintenance and the rate of HSCs replication.Atherosclerosis is an aging-related disease,and practically all humans develop atherosclerosis if they live long enough.Here we overview the potential roles of LTL dynamics in the imbalance between injurious oxidative stress/inflammation and endothelial repair during the pathogenesis of age-related atherosclerosis,and discuss the possibility that preventing accelerated cellular senescence is a potential target in prevention of atherosclerosis.

Effects of cannabinoid receptor type 2 on endogenous myocardial regeneration by activating cardiac progenitor cells in mouse infarcted heart

Cannabinoid receptor type 2(CB2)activation is recently reported to promote proliferation of some types of resident stem cells(e.g.,hematopoietic stem/progenitor cell or neural progenitor cell).Resident cardiac progenitor cell(CPC)activation and proliferation are crucial for endogenous cardiac regeneration and cardiac repair after myocardial infarction(MI).This study aims to explore the role and possible mechanisms of CB2receptor activation in enhancing myocardial repair.Our results revealed that CB2receptor agonist AM1241 can significantly increase CPCs by c-kit and Runx1 staining in ischemic myocardium as well as improve cardiomyocyte proliferation.AM1241 also decreased serum levels of MDA,TNF-αand IL-6 after MI.In addition,AM1241 can ameliorate left ventricular ejection fraction and fractional shortening,and reduce fibrosis.Moreover,AM1241 treatment markedly increased p-Akt and HO-1 expression,and promoted Nrf-2 nuclear translocation.However,PI3K inhibitor wortmannin eliminated these cardioprotective roles of AM1241.In conclusion,AM1241 could induce myocardial regeneration and improve cardiac function,which might be associated with PI3K/Akt/Nrf2 signaling pathway activation.Our findings may provide a promising strategy for cardiac endogenous regeneration after MI.

Angiopoietin-1 preconditioning enhances survival and functional recovery of mesenchymal stem cell transplantation

Objective： Mesenchymal stem cell （MSC） transplantation is a promising therapy for ischemic heart diseases. However, poor cell survival after transplantation greatly limits the therapeutic efficacy of MSCs. The purpose of this study was to investigate the protective effect of angiopoietin-1 （Angl） preconditioning on MSC survival and sub- sequent heart function improvement after transplantation. Methods： MSCs were cultured with or without 50 ng/ml Angl in complete medium for 24 h prior to experiments on cell survival and transplantation. 3-（4,5- Dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide （MTT） and Hoechst staining were applied to evaluate MSC survival after serum deprivation in vitro, while cell survival in vivo was detected by terminal deoxynucleotidyl trans- ferase biotin-dUPT nick end labeling （TUNEL） assay 24 and 72 h after transplantation. Heart function and infarct size were measured four weeks later by small animal echocardiography and Masson＇s trichrome staining, respectively. Results： Angl preconditioning induced Akt phosphorylation and increased expression of Bcl-2 and the ratio of Bcl-2/Bax. In comparison with non-preconditioned MSCs, Angl-preconditioned cell survival was significantly in- creased while the apoptotic rate decreased in vitro. However, the PI3K/Akt pathway inhibitor, LY294002, abrogated the protective effect of Angl preconditioning. After transplantation, the Angl-preconditioned-MSC group showed a lower death rate, smaller infarct size, and better heart functional recovery compared to the non-preconditioned-MSC group. Conclusions： Angl preconditioning enhances MSC survival, contributing to further improvement of heart function.

Protective paracrine effect of mesenchymal stem cells on cardiomyocytes

Objective： The aim of this study was to test the protective effect of mesenchymal stem cells （MSCs） on cardiomyocytes in vitro and to investigate the anti-apoptotic signaling pathway. Methods： MSCs from Sprague-Dawley （SD） rats were separated and cultured. MSC medium was collected from MSCs （DMEM） under hypoxia. Cultured cardiomyocytes from neonatal cultured in serum-free Dulbecco＇s modified eagle medium SD rats were exposed to hypoxia/reoxygenation （H/R） and treated with MSC medium. The apoptotic cardiomyocytes were stained with Annexin-V-fluorescein isothiocyanate （FITC）, Hoechst 33342 and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling （TUNEL）. The mitochondrial transmembrane potential of cardiomyocytes was assessed using a fluorescence microscope. The expression of Bcl-2, Bax, cyto- chrome C, apoptosis-induced factor （AIF）, and caspase-3 was tested by Western blot analysis. Results： Our data demonstrated that MSC medium reduced H/R-induced cardiomyocyte apoptosis, increased the Bcl-2/Bax ratio, and reduced the release of cyto- chrome C and AIF from mitochondria into the cytosol. Conclusion： MSCs protected the cardiomyocytes from H/R-induced apoptosis through a mitochondrial pathway in a paracrine manner.

Growth factors induce the improved cardiac remodeling in autologous mesenchymal stem cell-implanted failing rat hearts

Therapeutically delivered mesenchymal stem cells (MSCs) improve ventricular remodeling. However,the mechanism underlying MSC cardiac remodeling has not been clearly determined. Congestive heart failure (CHF) was induced in rats by cauterization of the left ventricular free wall. MSCs were cultured from autologous bone marrow and injected into the border zone and the remote myocardium 5 d after injury. Ten weeks later,when compared with sham operation,CHF significantly increased nucleus mitotic index,capillary density,and expression of insulin-like growth factor 1,hepatocyte growth factor and vascular endothelial growth factor in the border zone (P<0.01) and decreased each of them in the remote myocardium (P<0.05 or P<0.01). MSC implantation in CHF dramatically elevated ex-pression of these growth factors in the remote myocardium and further elevated their expression in the border zone when compared with CHF without MSC addition (P<0.05 or P<0.01). This was paralleled by a higher nucleus mitotic index and a significantly increased capillary density both in the remote myocardium and in the border zone,and by a lower percentage of area of collagen and a higher percentage of area of myocardium in the border zone (P<0.05 or P<0.01),and cardiac remodeling markedly improved. Autologous MSC implantation promoted expression of growth factors in rat failing myocardium,which might enhance cardiomyogenesis and angiogenesis,and improved cardiac remodeling.